Pt Care 5: Module 3 - 5: Sexually Transmitted Diseases, Women's Health

Module 3: STDs

Module 3: STDs

Syphilis: Pathophysiology

• Causative organism: Treponema pallidum

- Spirochete – corkscrew thin shape

- Can only be viewed by dark field microscope

- Motile microaerophilic bacterium

- Difficult to grow

• Transmission: Sexual OR vertical

- invades the intracellular junction of the endothelium, resulting in hematogenous spread,

– Seeds multiple organs (including CNS)

• THREE STAGES

1. Stage 1: Single painful lesion (the chancre)

▪ At the site of inoculation

▪ HIGHLY INFECTIOUS

▪ 3 - 90 days after exposure

2. Stage 2: Body Rash

▪ INFECTIOUS

▪ 4 - 10 weeks after initial infection

3. Stage 3: Affects internal organs (Cardiovascular syphilis and Gummatous lesions)

▪ 3 - 15 years after initial infection

▪ Inflammation at any organ

• Latent syphilis: Without treatment, the host suppresses the infection (asymptomatic)

• Categories

– Early latent: < 1 year duration (25% risk of spontaneous mucocutaneous relapse) - potentially infectious

• Greater risk of relapse to secondary syphilis

– Late latent: ≥ 1 year duration

• Considered non-infectious, although the patient remains a host

• ≈ 20- 30% progress to neurosyphilis or tertiary syphilis

• Despite being asymptomatic, all patients need treatment

– No way to predict which patients will experience disease progression

• Neurosyphilis - Encompasses patient with CSF abnormalities consistent with CNS infection

- Can occur at any stage

- Most patients have no CNS symptoms

• Ocular and otosyphilis syphilis can occur at any stage of syphilis

Syphilis: Testing

• Two types

1. Non-treponemal (qualitative and quantitative report) - problem with false-positives and false-negatives due to prozone effect

• E.g. Venereal Disease Research Laboratory [VDRL] or rapid plasma reagin [RPR] test

• Qualitative and quantitative

• Significant clinical response: A fourfold decrease in titer

2. Treponemal (qualitative report)

• E.g. T. pallidum passive particle agglutination [TP-PA] assay, various EIAs, chemiluminescence immunoassays [CIAs] and immunoblots, or rapid treponemal assays

• Measures antibodies and is qualitative only

• Used to confirm diagnosis

• Can distinguish active infection

• The use of only one type of serologic test is insufficient for diagnosis

– False-positive nontreponemal results in persons without syphilis or previously treated syphilis

• HIV, autoimmune conditions, immunizations, pregnancy, injection drug use

– False-negative results in persons tested during primary syphilis (i.e., tested too early)

• Need both types to confirm diagnosis

Syphilis: Treatment

• Primary, Secondary, early latent

★ Benzathine PCN G 2.4 MU IM x 1 dose

★ PCN Allergy Alternative: Doxycycline, Ceftriaxone

• Late latent, Tertiary without CNS involvement, Treatment failure without CNS involvement

★ Benzathine PCN G 2.4 MU IM weekly x 3 doses (total 7.2 MU)

★ PCN Allergy Alternative: Doxycycline

• Pregnancy

★ Penicillin G

(Emerging evidence indicates that additional therapy is beneficial for pregnant women to prevent congenital syphilis. For women who have primary,secondary, or early latent syphilis, a second dose of benzathine penicillin G 2.4 million units IM can be administered 1 week after the initial dose)

★ PCN Allergy Alternative: Desensitize

• USE LA Bicillin

• Can have Jarisch-Herxheimer Reaction 24 hours after initiation of syphilis treatment

• Acute febrile reaction

– Headache

– Myalgia

– Fever

• All sexual partners in the preceding 90 days should be referred

Neurosyphilis, Ocular Syphilis, and Otosyphilis Treatment

• Recommended:

– Aqueous crystalline penicillin G 18

–24 million units per day, administered as 3–4 million units IV every 4 hours or continuous infusion for 10–14 days

• Alternative regimen if compliance can be ensured:

– Procaine penicillin G 2.4 million units IM once daily Plus Probenecid* 500 mg orally 4 times/day (both for 10–14 days)

- Probencid extends the half-life of penicillin G

Neurosyphilis

• Encompasses patient with CSF abnormalities consistent with CNS infection

- Can occur at any stage

- Most patients have no CNS symptoms

• Symptoms

– Early CNS disease manifests as

• Meningitis

• Ophthalmic involvement (conjunctivitis to retinitis)

• Stroke

• Cranial nerve dysfunction

• Altered mental status

– Late onset CNS disease

• General paresis

• Tabes dorsalis

• Ocular involvement

If a patient is late latent (greater than 1 year duration), and is considered non-infectious, should they require treatment for syphilis?

YES! Despite being asymptomatic, all patients need treatment

- No way to predict which patients will experience disease progression

What are the two commonalities between neurosyphilis, ocular syphilis and otosyphilis?

All of them can occur at any stage and all have the same treatment regimen

Syphilis: Management of Sex Partners

For sex partners of patients with syphilis in any stage

Draw syphilis serology

Perform physical exam

For sex partners of patients with primary, secondary, or early latent syphilis

Treat presumptively as for early syphilis at the time of examination, unless the nontreponemal test result is known and negative and the last sexual contact with the patient is > 90 days prior to examination.

Syphilis: Pregnancy

• May lead to low birth weight or spontaneous abortion or still birth

Chlamydia trachomatis

• Gram-negative coccoid

• Obligate intracellular bacteria

• Exists in two forms

– Extracellular infectious elementary body (EB)

– Intracellular non-infectious reticulate body (RB)

• Coinfection with N. gonorrhoeae is common

• Most common in women 15 - 24 YO

• Transmission: Sexual and vertical

• Symptoms: Often asymptomatic in BOTH men and women

• Mens' symptoms if present: Urethritis

- Complications: Epididymitis, reactive arthritis, conjunctivitis, proctitis, lymphogranuloma venereum

• Women's symptoms if present: Urethritis, local signs of infection, dysuria, and frequency

- Complications: Pelvic inflammatory disease, Perihepatitis (Fitz-Hugh-Curtis Syndrome), Reactive arthritis, conjunctivitis, proctitis, lymphogranuloma venereum

• Annual screening of all sexually active women < 25 yrs is recommended

• Testing: NAAT

- Women: Vaginal swab

- Men: First-void urine

• Treatment:

★ Doxycycline 100 mg PO BID x 7 days

★ Alternative: Azithromycin, Levofloxacin

- Erythromycin is no longer recommended because of the frequency of gastrointestinal side effects, which can result in nonadherence.

★ Pregnant: Azithromycin 1 gm PO X 1 dose

★ Alternative: Amoxicillin

• To minimize transmission, abstain from intercourse for 7 days

• Test-of-cure is ONLY recommended for pregnant women, but ALL patients should be screened in 3 months to assess for re-infection

• Notify partner from 60 days ago

• Patients with chlamydia diagnosis should be tested for other STIs (Gonorrhea, HIV, and syphilis

Gonorrhea

• Gram-negative coccoid

diplococci bacterium Neisseria gonorrhoeae that prefentially binds to epithelial cells

• Coinfection with Chlamydia is common

• Most common in women 15 - 24 YO

• Transmission: Sexual and vertical

• Mens' symptoms: Urethritis

– Purulent or mucopurulent discharge

– Urethral discomfort

- Complications: Epididymitis, pharyngeal infection, anorectal infection, conjunctivitis, disseminated gonococcal infection (women > men)

• Women's Symptoms:

- Often asymptomatic

- Non-specific symptoms

• Abnormal vaginal discharge

• Intermenstrual bleeding

• Lower abdominal pain

• Dyspareunia

- Urethritis

- Complications: Accessory gland infection (Bartholin's glands), PID, perihepatitis (Fitz-Hugh-Curtis syndrome), pharyngeal infection, anorectal infection, conjunctivitis, disseminated gonococcal infection (women > men)

• Annual screening of all sexually active women < 25 yrs is recommended

• Testing: NAAT

- Women: Vaginal swab

- Men: First-void urine

- Can do cultures for susceptibility testing results

• Notify partner from 60 days ago

• Patients with chlamydia diagnosis should be tested for other STIs (Gonorrhea, HIV, and syphilis

Gonorrhea: Treatment

Treatment

• Uncomplicated Gonococcal infections of the Cervix, Ureathra and Rectum, Pharynx

★ Cefriaxone < 150 kg: 500 mg IM x 1 dose; > 150 kg: 1 g IM x 1 dose +/- doxy for chlamydia

★ Cephalosporin/PCN allergy: Gentamicin 240 mg IM x 1 dose PLUS Azithromycin 2 gm PO x 1 dose (will not work for infection of the pharynx)

• Conjunctivitis

★ Cefriaxone: 1 g IM x 1 dose +/- doxy for chlamydia

• Desseminated Gonococcal Infection

★ Cefriaxone: 1 g IM/IV daily for at least 7 days

• Gonococcal Ophthalmia Neonatorum Prophylaxis

★ Erythromycin (0.5%) ophthalmic ointment at birth

• To minimize transmission, abstain from intercourse for 7 days

• Test-of-cure is ONLY for:

• Patients with treatment failure or reinfection

• All patients with pharyngeal gonococcal infection

• But ALL patients should be screened in 3 months to assess for re-infection OR if symptoms persist after treatment

Vaginitis

• Polymicrobial clinical syndrome resulting from the loss of lactobacilli and replaced with high concentrations of anaerobes

• Often asymptomatic

• Lactobacilli are replaced by

– Gardnerella vaginalis

– Prevotella sp

• Several diagnostic tests

– Point-of-care testing

• Amsel criteria

• OSOM BV Blue test,

– Nucleic Acid Amplification Tests (NAAT)

– Saline wet mount

– Potassium hydroxide (KOH) preparation and Whiff Test

– Litmus testing for pH of vaginal fluid

Treatment

• Treatment of asymptomatic women (including pregnant women) is not recommended

★ Metronidazole 500 mg PO BID X 7 days

OR

★ Metronidazole gel 0.75%, one full applicator (5g) intravaginally daily X 5 days

OR

★ Clindamycin cream 2%, one full applicator (5 g) intravaginally nightly X 7 days

– Preferred option for women who are allergic or intolerant to metronidazole

★ Pregnant Women: Metronidazole 250 mg PO 3 times/day regimen or 500 mg PO BID for 7 days (same as non-pregnant)

• Clindamycin cream is oil-based and may weaken latex condoms or diaphragms for up to 5 days after use

• Avoid tinidazole in pregnancy

• First Recurrence

– Retreatment with the same recommended regimen

– Using a different recommended treatment regimen

Trichomoniasis

• Trichomonas vaginalis (T. vaginalis)

– single-celled, flagellated anaerobic protozoan parasite

– Only known protozoan parasite that iinfects the genital tract

• Predominantly spread through sexual contact

– Vertical transmission is possible

• Predominantly asymptomatic

• Men: urethritis, epididymitis, or prostatitis

• Women: vaginal discharge, malodorous, or“frothy” gray or yellow-green vaginal discharge with or without vulvar irritation

• Pelvic examination may show cervical petechiae (“strawberry cervix”) which strongly suggests a diagnosis of trichomoniasis

– Occurs in fewer than 5% of women with trichomoniasis

• Testing: NAAT are recommended for detecting trichomonas (urine, endometrial swab, vaginal swab)

Treatment

• Treatment of asymptomatic women (including pregnant women) is not recommended

★ Women (including pregnant): Metronidazole 500 mg PO BID X 7 days

★ Men: Metronidazole 2 g X 1 dose

OR

• Alternative for women and men: Tinidazole 2 gm PO X 1 dose

– Avoid in pregnant women

• Unlike BV, topical therapy is not recommended due to poor urethral and perivaginal gland penetration

• If someone has HIV, they should be tested for T. vaginalis

• Retesting is recommended for all sexually active women within 3 months of treatment

Herpes Simplex Virus

• Genital herpes is a chronic, lifelong viral infection

• Two HSV serotypes

– HSV-1 & HSV-2

– HSV-1: Most cases of oropharyngeal herpes

– HSV-2: Most cases of recurrent genital herpes

• Most people are unaware they are infected

• Virus enters cytolytic replication and is taken up by sensory nerve axons and transported in a retrograde manner to the neurons, and confers lifelong infection

• Lesions are not limited to initial infected site since virus can travel through axons

• Primary episode: Bilateral clusters of erythematous papules and vesicles on the external genitalia that last 2 - 3 weeks, progress from vesicle pustule to wet ulcers to dry crusts

• Up to 90% of patients with symptomatic HSV-2 will have a recurrence within the 1st year

• Mild, localized symptoms that resolve within 3 to 5 days after onset

• Viral prodrome

– Symptoms arise before lesions

– Includes tingling, burning, itching, paresthesia, and pain around the lumbosacral dermatomes

• Lesions heal in 5 – 10 days without treatment

• Extragenital presentations (usually in immunocompromised)

- Aseptic meningitis (HSV-2)

- HSV encephalitis (HSV-1)

- Pneumonitis

• Testing: NAAT preferred, can use culture testing to determine susceptibility

Herpes Simplex Virus: Treatment

• First episode should always be treated

• Treatment options*

★ Acyclovir 400 mg PO TID X 7 – 10 days

OR

★ Valacyclovir 1 gm PO BID X 7 – 10 days

OR

★ Famciclovir 250 mg PO TID X 7 – 10 days

• Suppressive Therapy– Reduces HSV-2 shedding by 70 – 80%

★ Acyclovir 400 mg PO BID

OR

★ Valacyclovir 500 mg PO QD

OR

★ Valacyclovir 1 gm PO QD

OR

★ Famciclovir 250 mg PO BID

• Episodic Therapy– Initiation of therapy within 1 day of lesion onset or during prodrome that precedes outbreaks

Acyclovir

★800 mg PO BID x 5 days

★800 mg PO TID x 2 days

OR

Valcyclovir

★500 mg PO BID x 3 days

★1 g PO QD x 5 days

• Intravenous therapy should be used in the following scenarios

:– Disseminated infection

– Pneumonitis

– Hepatitis

– Meningoencephalitis

★ Acyclovir 5 – 10 mg/kg IV every 8 hrs

★ Use IBW

★ Renal adjustment needed

• Treatment options for resistance

– Foscarnet (40 – 80 mg/kg IV every 8 hours) until clinical resolution is attained

– Cidofovir 5mg/kg once weekly might also be an effective

– Imiquimod 5% cream applied to the lesion for 8 hours 3 times/week until clinical resolution

– Topical cidofovir gel 1% applied to lesions 2–4 times daily(compounded)– Foscarnet and cidofovir are both nephrotoxic and require close monitoring of renal function

Module 4: Women's Health Part 1

Module 4: Women's Health Part 1

Diagnosis - Amsel Criteria

• BV is commonly diagnosed in clinical settings usingthe Amsel criteria

• Clinical diagnosis if 3 of the following 4 criteria:

– Vaginal pH greater than 4.5

– The presence of “clue cells” (bacterial clumping) in at least 20% of vaginal epithelial cells per high power field viewed on saline microscopy

– Positive amine, “whiff” or “fishy odor” test (liberation of biologic amines with or without the addition of 10%KOH)

– Homogeneous, nonviscous, milky-white discharge adherent to the vaginal walls

Ovarian Cycle

Follicular stage

• Proliferative phase where estrogen dominates

• Many growing follicles with ova

- One follicle matures and becomes dominant

• Secrete Estradiol >> androgens

• Results in + feedback at midcycle for FSH and LH, and there is also a autocrine + feedback loop intially between estradiol and FSH, but then a - feedback loop where high levels of inhibin and estrogen decreases the amount of FSH

Luteal phase

• Secretory phase where progesterone dominates

• One single corpus luteum

• Secretes progesterone and estradiol

• Results in - feedback of LH and FSH

What is the menstrual cycle day 1?

First day of menses

1st phase of menstrual cycle is _________ and 2nd phase is _______________.

follicular phase; luteal phase

(ovulation occurs mid-cycle in day 14

What phase is the most constant part of the cycle?

Luteal phase

Menstrual cycle:

• FSH stimulates many follicles to develop

• LH stimulate A production in the thecal cell, FSH stimulate conversion A to E via aromatase in the granular cells when the mature follicle is ready to ovulate

• Smaller follicles regress as ↑E and inhibin → ↓ plasma FSH NEGATIVE FEEDBACK

• DOMINANT FOLLICLE: most aromatase (most estrogen with the least androgen), most E secretion

- In dominant follicle, E has stimulated FSH receptors, most sensitive to the low FSH AUTOCRINE POSITIVE FEEDBACK since FSH increases aromatase activity and also causes the maturation of the ova by providing nutrients and local estrogen increases FSH receptors

• Dominant follicle at Midcycle: ↑↑↑E → POSITIVE FEEDBACK → ↑↑↑LH/FSH → OVULATION (ova released from follicle)

• After ovulation, the CORPUS LUTEUM is formed; and LH stimulates P, E, and inhibin

- P + E secretion leads to NEGATIVE FEEDBACK, ↓ LH/FSH

• When CL regresses, E and P fall → menses

• Cycle “restarts” when low E and P allow FSH to go up, stimulating follicular growth

Uterine Cycle (Proliferative vs. Secretory)

Follicular phase/ Proliferative phase

• Growth of endometrium

• Growth of vasculature

• Growth of endometrial glands

ESTROGEN EFFECTS

Luteal phase/Secretory phase

• Secretion from endometrial glands

• Secrets nutrients to support a fertilized embryo if fertilization occurs

PROGESTERONE EFFECTS

Pulses in the follicular phase vs. luteal phase

• Less frequent pulses of GnRH favor release of FSH

• More frequent pulses favor secretion of LH

Loss of E and P stimulation =

menses (at the end of the luteal stage with FSH and LH go up again)

What does the mature follicle become after releasing an ova?

A corpus luteum that secretes progesterone and estradiol

Ovarian Hormone Synthesis

• LH acts on theca cells to produce androgens

• Granulosa cells convert androgens to estrogens via aromatase

• FSH enhances activity of aromatase

• Estrogen production (estradiol) is much greater than androgen

How long does the estrogen level need to be high for to trigger the LH surge?

At least 2 days

Ovarian Effects on FSH and LH

Follicular phase

– Dominant follicle produces high levels of estradiol and inhibin

– Negative feedback on FSH secretion

– High levels of estrogen at end of follicular phase

• Positive feedback when high levels of E for > 2 days

• Triggers LH surge and follicular rupture

• Ovulation occurs 24-36 hours after LH surge

Luteal phase

– LH causes formation of CL

– LH stimulates CL to secrete P and E (also inhibin)

– P has negative feedback on LH secretion (reduces GnRH pulses)

– E and inhibin prevent the release of FSH

Effect of Estrogen on Target Organs

• Breast – growth and differentiation

• Ovary – proliferation of granulosa cells

• Uterus

– Proliferation of endometrium

– Production of thin cervical mucus which makes it easier for the sperm to swim to the egg easier

• Bone

– Promotion of bone growth, epiphyseal closure

– Reduction of osteoclast formation and activity

• Liver

– Reduced total cholesterol and LDL

– Increased HDL

• CNS - neuroprotective

Effect of Progesterone on Target Organs

• Reproductive tract (uterus and ovary)

– Important in attainment and maintenance of pregnancy

– Promotes implantation

– Helps to maintain pregnancy

• Brain

– Regulates body temperature

– Body temp increased in luteal phase

– Influences sexual behavior

Menopause

• Permanent cessation of menstrual cycle

• Results from loss of ovarian follicular response to FSH

• In perimenopause, cycles are irregular

• After menopause

– High levels of FSH; low levels of estradiol

– Predominant estrogen is estrone (from aromatization of adrenal androstenedione)

• Atrophy of estrogen-dependent tissues

– Vaginal mucosa

– Breast

– Loss of bone mass

• Hot flashes

___________ cells make estrogen and ________ cells make androgens;

Granulosa; theca

Why does estrogen increase the risk of DVT?

Since it stimulates the production of coagulation factors

Human chorionic gonadotropin (hCG)

Hormone produced by the placenta to sustain pregnancy by stimulating the ovaries to produce estrogen and progesterone

Two Estrogen Receptors: ER⍺ and ERβ

Two pathways for activation:

1. In the nucleus

2. In the cell membrane

After activation, gene transcription occurs and body responds to change at the receptor

Oral Estrogens (Two Types)

1. Natural estrogens

– Estradiol (bioidentical)•

Example: 17-B estradiol (Estrace)

• Synthetic estrogens

– Ethinyl Estradiol (most common)

– Mestranol: Prodrug of ethinyl estradiol

– Conjugated equine estrogens

• Example: Premarin

Pharmacokinetics of Oral Estradiol

• Absorption

– Rapidly absorbed in small intestine

• Distribution

– HIGHLY protein bound (SHBG, albumin)

• Metabolism

– HIGH first-pass metabolism in the liver

– Metabolized by CYP3A4 & CYP1A2

.– Undergoes enterohepatic recirculation

• Excretion

– Renal (urine) and biliary (fecal) excretion of metabolites. Half-life: 12-16 hours for estradiol due to enterohepatic recirculation

Clinical Considerations:

• Effective for menopause symptoms.

• Increases SHBG → reduces free testosterone (may improve acne but decrease libido).

★ Higher risk of VTE, stroke, and gallbladder disease due to hepatic metabolism.

★ Increases triglycerides and C-reactive protein (CRP), affecting cardiovascular risk.

Pharmacokinetics of Transdermal Estradiol

• Agents

- Estradiol patches (Vivelle-Dot, Climera, minivelle)

- Estradiol gels (Divigel, estrogel)

- Estradiol sprays (Evamist)

- Compounded creams

• Absorption

– Directly absorbed through skin into systemic circulation, bypassing first-pass metabolism.

• Distribution

– More stable plasma estrogen levels than oral estrogen

• Metabolism

– Converted to estrone in peripheral tissues and metabolized in the liver. Avoids enterohepatic recirculation. (unlike oral)

• Excretion

– Renal (urine) with minor biliary excretion. Half-life: 4-6 hours per dose, with steady-state achieved in 48-72 hours since it avoids enterhepatic recirculation

Clinical Considerations:

• Bypasses first pass metabolism --> lower VTE and stroke risk

• Minimal effect on TGs and liver proteins (less impact on clotting and inflammation)

• Preferred for high-risk patients (e.g., history of clotting disorders, migraine with aura).

★ Patch site reactions (redness, irritation) may occur

★ Less effect on SHBG → may not lower testosterone levels as much as oral estrogen.

Pharmacokinetics of Vaginal Estradiol

• Agents

- Estradiol vaginal cream (Estrace)

- Estradiol vaginal ring (Estring, Femring)

- Vaginal tablets (Vagifem, Imvexxy)

- Compounded creams (various)

• Absorption

– Very minimal systemic absorption with low dose formulations

– some systemic absorption occurs with higher-dose vaginal rings (Femring)

• Distribution

– Localized effect in the vaginal epithelium, urethra, and bladder

• Metabolism

– Minimal hepatic metabolism

• Excretion

– Primarily through vaginal epithelial turnover

Clinical Considerations:

• Best for treating genitourinary syndrome ofmenopause (GSM) (e.g., vaginal dryness, atrophy, painful intercourse, urinary symptoms).

• Minimal systemic side effects with low doses (low risk for VTE, stroke).

★ Higher-dose vaginal estrogen (Femring) behaves more like systemic estrogen → potential systemic effects.

★ Femring requires progestogen or progesterone if the patient has an intact uterus.

What is the vaginal estradiol that requires progesterone?

FEMRING

Pharmacokinetics of Injectable Estrogens

• Agents

- Estradiol valerate (Delestrogen)

- Estradiol cypionate (Depo-Estradiol)

• Absorption

– Injected intramuscularly (IM) or subcutaneously (SC) for slow, extended release into systemic circulation

• Distribution

– High circulating estradiol levels, with peaks and troughs depending on dosing frequency

• Metabolism

– Converted to estrone and estriol in peripheral tissues, then metabolized by the liver (CYP3A4)

• Excretion

– Primarily renal excretion, with a prolonged half-life of 4-20 days depending on formulation

Clinical Considerations:

• Provides sustained estrogen levels (longer

duration per dose).

• Useful for patients who struggle with adherence to daily regimens

★ Fluctuations in hormone levels (peaks and troughs) may cause mood swings or breast tenderness.

★ Higher systemic estrogen exposure → potentially increased risk of VTE and estrogen-sensitive cancers.

Key Differences between Estradiol Routes of Administration

Clinical Considerations:

• For menopausal symptoms + high clot risk: Transdermal estrogen (patch, gel, spray)

• For vaginal dryness only: Low-dose vaginal estrogen (cream, tablet, ring)

• For patients who prefer less frequent dosing: Injectable estrogen (long-acting but may have fluctuating levels).

• If you want strong SHBG effect: Use oral

Pharmacokinetics of Synthetic Estrogens

• Structurally modified estrogens to enhance potency and half-life.

• Agents

- Ethinyl Estradiol (EE)

- Conjugated Estrogens (CEs) aka Premarin

• Absorption

– Oral, transdermal, injectable

• Distribution

– Strong binding to SHBG

– Also increases SHBG → Reduces free testosterone (good for acne)

• Metabolism

– Resist first-pass metabolism, increasing hepatic estrogenic effects

• Excretion

– Primarily biliary excretion, undergoes enterohepatic recirculation, prolonging half-life (and increasing clot risk)

Clinical Considerations:

• Longer half-life, increased potency

• More effective for contraception due to suppression of ovulation

• Lower doses needed due to increased stability

★ Increased risk of thromboembolism (VTE, stroke) due to hepatic metabolism

★ Stronger effects on SHBG → May decrease free testosterone & libido

★ Less physiologic compared to bioidentical estradiol

ADME of Progestins

(See Image)

• Duration of action:

Oral: ~5-24 hours, varies by type

IM: 3 months

Transdermal: variable (daily or weekly application needed)

IUD: 5 years

Progestins (Progestogens)

• “Synthetic” chemically modified versions of progesterone that interact with progesterone receptors (PRs)

• Used in contraception, menopause hormone therapy (MHT), and treatment of endometrial disorders

• Synthetic progestins primarily exert their effects by binding to progesterone receptors (PR-A and PR-B), leading to changes in gene transcription.

• Depending on the type of progestin, some also bind to androgen receptors, mineralocorticoid receptors, and glucocorticoid receptors

• MOA (6 Things)

1. Inhibition of Gonadotropin Release (LH & FSH Suppression)

• Inhibit LH and FSH

• Block LH surge (prevents ovulation)

2. Endometrial changes

• Endometrial atrophy makes the tissue less receptive to implantation (endometrial thinning)

• Thicken cervical mucus to prevent sperm penetration of the egg

3. Androgenic receptor activity

• Norethindrone, levonorgestrel bind to the androgen receptor

• Decreased SHBG, greater potential for acne, and potential lipid alterations

4. Anti-Estrogenic Effects

• Oppose estrogen-driven endometrial proliferation, reducing the risk of endometrial hyperplasia and cancer in MHT.

• They achieve this by modulating estrogen receptor expression, inhibiting estrogen-driven endometrial proliferation, and affecting estrogen metabolism (do NOT directly bind to the ER

5. Anti-Mineralocorticoid Effects

• Drosperinone

• Blocks aldosterone, leading to mild diuretic effects and reduced fluid retention

6. Glucocorticoid Activity

• Medroxyprogesterone acetate (MPA)

– Insulin resistance, appetite stimulation, and bone loss

____________ are used for contraception whereas progesterone are used more for menopuase hormone therapy (MHT).

Progestins

1st and 2nd Generation Progestins

(See Image)

3rd and 4th Generation Progestins

(See Image)

What progestins have an increased risk of thrombosis?

Desogestrel (3rd Gen), drospirenone (4th Gen) have BBW

Pros and Cons of Progestins

Pros

• Stronger inhibition of ovulation (more effective for contraception than progesterone)

• More stable duration of action than progesterone

• Varied effects allow customization (e.g., anti-androgenic for acne, androgenic for libido enhancement)

Cons

• Some increase LDL and lower HDL (e.g., norethindrone, levonorgestrel)

• Some have increased risk of thrombosis (e.g.,desogestrel, drospirenone)

Progesterone (ADME, MOA)

• Considered “natural” because it is identical to the progesterone produced by the ovaries.

• Oral (micronized), vaginal, and injectable formulations

- Micronized to improve BA

• Oral (mainly) and vaginal progesterone becomes allopregnanolone which causes a calming sensation

• MOA: Also binds to PR-A and PR-B

1. Endometrial Regulation & Pregnancy Maintenance

• Prepares the endometrium for implantation by creating a secretory environment

• Supports pregnancy by maintaining the uterine lining and inhibiting uterine contractions.

• Suppresses estrogen-driven proliferation to prevent endometrial hyperplasia (but to a lesser degree than progestins)

2. Cervical Mucus Thickening

• Increases the viscosity of cervical mucus (but less than progestins) to create the cervical mucus plug and protect pregnancy

3. Neurosteroid Activity & GABA Modulation in ORAL progesterone

• Metabolized into allopregnanolone, which acts on GABA-A receptors in the brain, exerting calming, anxiolytic, and sleep-promoting effects

• Modulates mood (protective against perimenopausal mood swings and anxiety)

4. Bone & Cardiovascular Effects

• Supports bone mineralization by modulating osteoblast activity.

• Unlike synthetic progestins, it does not negatively impact lipid metabolism (it maintains HDL levels and does not increase LDL).

5. No Androgenic Activity & Minimal Glucocorticoid Activity

• Unlike some progestins, progesterone does not bind to androgen receptors and does not worsen lipid profiles

• Minimal glucocorticoid activity (does not promote insulin resistance like some progestins).

Allopregnanolone

What oral and vaginal NATURAL progesterone become which acts on GABA-A receptors in the brain, exerting calming, anxiolytic, and sleep-promoting effects

True/False: Progesterone worsens lipid panels.

FALSE, it does not bind to androgen receptors, therefore does not worsen lipid profiles. However, PROGESTINs do worsen lipid panels, especially levonorgesterol and norethindrone

Pro & Cons of Progesterone

Pros

• Less impact on lipid metabolism than synthetic progestins

• Supports pregnancy and endometrial stability

• No androgenic effect

• May improve sleep and mood via GABA-A receptor modulation

Cons

• Short half-life → Requires higher doses or sustained-release formulations

• Oral progesterone can cause drowsiness (due to GABA effects)

Steroid Structure and Nomenclature

• 3, 5 and 17 position are important

• Alpha phase is moving away and beta phase is towards you

Different structural classes of steroids

• Structural classes of steroid hormones

– Vary in presence of carbon chain on the D ring and number of carbons in skeleton

• Pregnane - 21 C

• Androstane - 19 C

• Estrane - 18 C

Steroid Hormone Biosynthesis

(See Image)

• Start off with cholesterol

• DHEA is converted by 3β-HSD into androstenedione (coverts ketone to alcohol)

• Androstenedione is converted by aromatase (CYP19) into estrone (introduces aromatic group)

• Androstenedione is converted by 17β-HSD into testosterone (coverts ketone to alcohol)

• Estrone is converted by 17β-HSD into estradiol reversibly

Recognize different structural classes of aromatase inhibitors and know how they interact with the enzyme

• Used in treatment of breast cancer

• Type 1: Steroid inhibitor that binds at active site - using a mechanism-based inhibitor where the aromatase enzyme will attack the double bond and lead to covalent modification (DOUBLE BOND STICKING OUT)

• Type 2: Non-steroid inhibitor that has a heterocycle that binds to the heme iron that is involved in the oxidation process (TRIAZOLE GROUP)

Med Chem: Natural Occurring Estrogens

• Relative affinities for estrogen receptors ERα or ERß: E2 (estradiol) >> E1 (estrone) ~ E3 (estriol) >> E4 (esetrol)

• Estradiol is the most potent

Estrogen Pharmacophore

• Phenol – hydrogen bond donor

• 17ß hydroxyl – hydrogen bond acceptor

• Relatively flat hydrophobic spacer

Med Chem: Equine Estrogens

• Unique estrogens equilin and equilenin

– Conjugated estrogens (e.g. Premarin)

• Sulfate conjugates obtained from pregnant mare urine, estrone sulfate major component

– Esterified estrogens (Estratab, Menest)

• Synthetic mixture, different % composition

– Used in treatment of menopause symptoms

• Has a sulfate group!!

• Conjugates inactive

– Sulfates in conjugated and esterified estrogens act as prodrugs – cleaved by sulfatases

Recognize the natural estrogen incorporated into oral contraceptives

• Ethinyl estradiol primary estrogen used

– 17a-ethinyl group blocks oxidation of 17ß-hydroxyl to estrone

– 3-Methoxy derivative mestranol also used in an OC

• Estetrol (E4) - pictured

– Naturally occurring estrogen produced by fetal liver

• 10-20 times less potent than ethinyl estradiol

• Appears to have estrogen antagonist activity in breast tissue

– Combination product containing estetrol (Nextstellis) approved in 2021

• First new type of estrogen approved by FDA in >50 years

• Synthesized from sterol extracted from soybean

Recognize the structural modification to estradiol used to block metabolism

• 17α-ethinyl group blocks oxidation of 17ß-hydroxyl (of estradiol) to estrone

- Estradiol is more potent, so this ethinyl (triple bond group) stabilizes it

Progestins - Pregnanes

• 17a-acetoxyprotesterone derivatives

– Progesterone almost complete first pass metabolism

– 17a-Acyl group not prodrug, slows metabolism of 20-ketone

– Clinically used substituted at 6 position

• Medroxyprogesterone acetate – injection lasting 3 months

• Segesterone acetate

– 19-Norprogesterone analog

– 16-Methylene, 17a-acetoxy groups

– Low oral bioavailability • used in combination with ethinyl estradiol in a vaginal ring (Annovera)

Recognize structural modification in norgestrel and the difference between norgestrel and levonorgestrel

• Norgestrel has C-18 ethyl group rather than C18 methyl group – made synthetically

– Norgestrel – racemic mixture

– Levonorgestrel – active enantiomer

• Has the 17a-ethynyl group

Recognize progestins that act as prodrugs

• Prodrugs of norethindrone include:

▪ Norethindrone acetate - rapidly hydrolyzed by esterases to norethindrone

▪ Ethynodiol diacetate - rapidly hydrolyzed by esterases to norethindrone

▪ Lynestrenol

Progestin antagonists- Recognize key structural modification that imparts antagonist activity

• Mifepristone

– 11ß side chain thought to destabilize progesterone receptor agonist conformation - gives ANTAGONIST ACTIVITY

– It also is a potent glucocorticoid antagonist

• Approved for treating certain Cushing’s syndrome patients

– Used as abortifacient in combination with the prostaglandin misoprostol

• Ulipristal acetate

– Lower glucocorticoid antagonist

– Used as emergency contraceptive and for treatment of uterine fibroids

__________ are primary progestins used.

Estranes (17a-ethynyl group in almost all of these progestins)

Contraceptive Options

• Estrogen and Progestin

– Combination oral contraceptive (COC) pill

– Contraceptive patch

– Contraceptive ring

• Progestin Only

– Progestin-only pills

– Injectable medroxyprogesterone

– Subdermal implant

– Levonorgestrel intrauterine system

• Copper containing IUD

• Non-pharmacologic methods

– Condom

– Diaphragm

– Sponge

– Other

Combination oral contraceptives (COCs)

• Consists of estrogens (usually ethinyl estradiol) and a progestin

• MOA of Estrogen:

– Suppress release of FSH/LH

– Inhibit ovulation 95-99% of cycles

– Accelerate ovum transport

– Inhibit ovum implantation

– Estimated dose to suppress = 20-30mcg/24 hours

• Estrogen Dose Range: 10 - 50 mcg daily (typically 30 - 35 mcg/day)

▪ If Adolescents, < 110 lbs, > 35 years, perimenopausal – COC with 20 to 25 mcg EE

• MOA of Progestin:

– Thicken cervical mucus

– Inhibit spermatic enzymes

– Inhibit ovulation

• Most contain 28 pills (21 followed by 7 placebo or 24 followed by 4 placebo)

• Menstrual bleeding occurs when taking placebo pills

• Monophasic – active pills have same hormone content

• Multiphasic or sequential - amount of hormones in active pills varies

▪ Most common- 7/7/7 (Triphasic)

▪ 21/2/5

• Lower risk of cancer – 50% reduction after 5 years

– Endometrial (uterus)

– Ovarian

• But increases the risk of cervical cancer because patients are less likely to use a barrier method and can contract HPV and STDs

Drug Interactions

• Lower dose COCs = higher risk

• Enzyme inducers

– Rifampin

– Anticonvulsants

• St. John’s wort (3A4 inducer)

• Antibiotics – controversial

• Anticoagulants

Adverse Effects of Estrogen

• Breast tenderness

• Nausea

• Vomiting

• Hypertension

• Thromboembolism

Adverse Effects of Progestin

• Acne, oily skin

• Depression

• Fatigue, lethargy

• Hirsutism

• Libido

• Weight gain

Severe AEs of COCs

• A - Abdominal pain

• C - Chest pain (SOB, coughing)

• H - Headache (severe HA, dizziness)

• E - Eye problems (seeing double, blurry vision)

• S - Severe Leg Pain (calf or thigh)

Progestins List

• Norethindrone

• Norethindrone acetate

• Norgestrel

• Levonorgestrel

• Norgestimate

• Desogestrel

• Drospirenone

• Dienogest

Which progestin has the highest androgenic activity?

Levonorgesterel

When should you lower the estrogen dose of the COC to 20 to 25 mcg EE rather than 35 mcg of less?

• Adolescents

• < 110 lbs

• > 35 years

• Perimenopausal

What should be used to decide if a BC is appropriate if the patient has coexisting medical conditions?

CDC Medical Eligibility Criteria

COCs and Acne

• Oral contraceptives may help acne

- Ethinyl estradiol (estrogen) increases synthesis of SHBG

• Choose progestin with low androgenic activity

- Norgestimate*

- Desogestrel

- Drospirenone*

- Dienogest

*Have an FDA indication for treating mild to moderate acne

When should you advice patients to take their birth control?

At night , since when patients have high levels of estrogens and are exposed to the sun, they can develop melasma

COCs - When to Start?

1. Sunday start (most common method)

– Start on the Sunday after menses begins

– Use back-up method for 1 week (one cycle?)

OR

2. Day 1 start

– Start on the first day of menses

– Back-up contraception not required

OR

3. Quick start

– Start ASAP (on day of office visit)

– Use back-up method for 1 week

– Pregnancy should be ruled out first

Recommended Actions After Late or Missed Combined Oral Contraceptives

• If one pill has been missed and it has been < 48 hrs, don't need to use additional contraceptive protection

• If two ore more consecutive pills have been missed OR it's been greater than 48 hrs then a pill has been missed, then will need to use barrier methods until 7 consecutive days of pills have been taken

COCs - Drug Interactions

• Lower dose COCs = higher risk

• Enzyme inducers

– Rifampin

– Anticonvulsants

• St. John’s wort (3A4 inducer)

• Antibiotics – controversial

• Anticoagulants

COCs - Adverse Effects

Adverse Effects of Estrogen

• Breast tenderness (because breasts have a lot of estrogen receptors)

• Nausea

• Vomiting

• Hypertension

• Thromboembolism

Adverse Effects of Progestin

• Acne, oily skin

• Depression

• Fatigue, lethargy

• Hirsutism

• Libido

• Weight gain (seen in high doses like in medroxyprogesterone)

Severe AEs of COCs

• A - Abdominal pain

▪ Possibly liver problem, gallbladder disease

• C - Chest pain (SOB, coughing)

▪ Possible pulmonary embolism, MI

• H - Headache (severe HA, dizziness)

▪ Possibly hypertension, stroke, migraine

• E - Eye problems (seeing double, blurry vision)

▪ Possibly stroke or hypertension

• S - Severe Leg Pain (calf or thigh)

▪ Possibly deep vein thrombosis

COCs and Breakthrough Bleeding

• Common after COC initiation

• Frequent reason for discontinuation

• May be related to missed pills

• Too little estrogen

– Breakthrough bleeding early in cycle

• Too little progestin

– Breakthrough bleeding late in cycle

• Continue for up to 3 months before change

Contraindications to COCs

Absolute

• Pregnancy

• Breast cancer

• Thromboembolism

• MI /ASCVD

• Over 35 and smoker (esp. > 15 cigs/day)

• Severe uncontrolled hypertension

– SBP ≥ 160, DBP ≥ 100

Relative

• Gallbladder disease

• Immobilization

• Under 35 and smoker

• Severe headaches

• Uncontrolled hypertension

– SBP 140-159 and/or DBP 90-99

Contraceptives with shorter hormone free interval

• Yaz

• Beyaz

• EE20/desogesterel (kariva)

• Ultra low dose (Lo Loesterin Fe)

• Nextstellis

• Shorter hormone-free interval = improved menstrual symptoms

Yasmin

• EE (30 mcg), drosperinone 3 mg

Yaz

• EE (20 mcg), drosperinone 3 mg

• Shorter hormone-free interval = improved menstrual symptoms

• 24/4 day regimen

Beyaz

• EE (20 mcg), drosperinone 3 mg + levomefolate calcium (folic acid derivative)

• Approved for symptom of PMDD

Drosperinone

– Related to spironolactone

–Antiandrogenic/antimineralocorticoid

– Monitor potassium

– Drug interactions

– Risk of clots ??

What electrolyte do you need to monitor if a patient is on drosperinone?

Potassium!

Nextstellis

• Plant derived estrogen

• Estetrol/drospterinone

• Estetrol (E4) derived from estrone in soy beans

• 24/5 day regimen (shorter hormone free interval)

Extended Cycle Contraception

• Seasonal (Jolessa)/Seasonique

• 30 mcg EE, 0.15 mg LNG

• 84 active pills, 7 placebo pills

• One cycle per season

• Seasonique – no placebo, 7 days of 10 mcg EE

• LoSeasonique – 20 mcg EE, 0.10 mg LNG, no placebo

• Another way to minimize PMS since endometrium thins out

Who are transdermal contraceptive patches CI in?

• Women over 35 who smoke

• Women with BMI ≥ 30 kg/m2

- Higher risk of blood clots compared to BMI < 30

Transdermal Contraceptive Patch (COCs)

• Norelgestromin 150 mcg/ EE 35 mcg contraceptive patch ( Xulane®, Zafemy)

• LNG 120 mcg/EE 30 mcg (Twirla®)

• Applied weekly for three weeks. where drug is released using a adhesive matrix system

• Change patch on same day each week and rotate the site

• Patch releases hormone for ~ 9 days

• Week four - patch-free

• Efficacy similar to COCs

• Apply to (1) Buttock (2) Abdomen (3) Upper torso (excluding breasts) and (4) Upper arm

- Absorption from these sites are considered equivalent

• Advantages

– Simple to use

– Good adherence

– Highly effective

• Disadvantages

– Patch detachment (use back-up if off for > 24 hrs)

– Reduced effectiveness

• Xulane > 90kg or >198 lbs

• Twirla BMI 25 to 30 kg/m2

– ↑ Estrogen exposure

• Risk of VTE about 10/15 per 10,000 women/year

• Risk of VTE still lower than with pregnancy

• Boxed warning - Contraindicated:

• Women over 35 who smoke

• Women with BMI ≥ 30 kg/m2

- Higher risk of blood clots compared to BMI < 30

Adverse Effects of Estrogen

• Breast tenderness (because breasts have a lot of estrogen receptors)

• Nausea

• Vomiting

• Hypertension

• Thromboembolism

Adverse Effects of Progestin

• Acne, oily skin

• Depression

• Fatigue, lethargy

• Hirsutism

• Libido

• Weight gain (seen in high doses like in medroxyprogesterone)

Severe AEs of COCs

• A - Abdominal pain

▪ Possibly liver problem, gallbladder disease

• C - Chest pain (SOB, coughing)

▪ Possible pulmonary embolism, MI

• H - Headache (severe HA, dizziness)

▪ Possibly hypertension, stroke, migraine

• E - Eye problems (seeing double, blurry vision)

▪ Possibly stroke or hypertension

• S - Severe Leg Pain (calf or thigh)

▪ Possibly deep vein thrombosis

Why can patches not be used for longer than a week?

Skin becomes macerated underneath and becomes compromised

Xulane- Administration

• If patch edge lifts up:

– Press with palm x 10 sec, smooth wrinkles. Replace if it cannot be fully affixed

• If patch wholly are partially off:

– If < 1 day: Reapply; if not sticking, apply a new patch immediately

– If > 1 day or unsure: New patch, new cycle with 7 day non-hormonal backup

• If discomfort or skin irritation:

– New patch to a new location until next change day

• When done, fold and discard

Progestin-Only Pill ("mini pill")

• Low-dose pill containing progestin only

• Progestin-only contraceptive MOA:

– Suppresses ovulation (inhibits LH surge)

– Thickens cervical mucus

– Inhibit spermatic enzymes

– Causes thinning of endometrium

• Active pill every day

• Norethindrone 0.35 mg – Camila®, Errin®, others

Advantages

• No estrogen side effects

• Minimal progestin side effects

• OK with breastfeeding

• OK for smokers

Disadvantages

• Less effective

– 40% continue to ovulate

• Complex instructions

• Strict compliance

• Irregular bleeding

• Lack of bleeding (amenorrhea)

Contraceptive Vaginal Ring (COCs)

• Ethinyl estradiol 15 mcg/etonogestrel 120 mcg (NuvaRing®, EluRyngTM , others)

• Ethinyl estradiol 13 mcg/segesterone 150 mcg (Annovera®)

• A drug reservoir (saturated solution) of etonogestrel and ethinyl estradiol is contained within a rate-controlling (releases in a zero-order fashion), 54 mm diameter, ethylene vinyl acetate polymer ring

• Left in place for three weeks (monthly) and 4th week ring free

– Nuva Ring – remove and discard in a safe manner

– Annovera – remove and clean with warm water and soap; dry, and store in case (reuse for a year)

• Adverse effects

– Headache

– Breast tenderness

– Nausea

– Local effects

• Irritation

• Leukorrhea

• Infection

• Storage considerations: Store any NuvaRing that won’t be used for at least 4 months in refrigerator

- Dispensed as a box of 3, with a 4-month* expiration date when stored at 25°C with the exception of Haloette which is good for 6 months (Eluruing and EnilloRing good for 4)

• Advantages

– Easy to use, inconspicuous

– Good for adherence

– Highly effective

• Disadvantages

– Slippage/expulsion

• Rinse and reinsert

• Use back-up method for 7 days

→ 3 hours out - NuvaRing

→ 2 hours out - Annovera

Adverse Effects of Estrogen

• Breast tenderness (because breasts have a lot of estrogen receptors)

• Nausea

• Vomiting

• Hypertension

• Thromboembolism

Adverse Effects of Progestin

• Acne, oily skin

• Depression

• Fatigue, lethargy

• Hirsutism

• Libido

• Weight gain (seen in high doses like in medroxyprogesterone)

Severe AEs of COCs

• A - Abdominal pain

• C - Chest pain (SOB, coughing)

• H - Headache (severe HA, dizziness)

• E - Eye problems (seeing double, blurry vision)

• S - Severe Leg Pain (calf or thigh)

Nuvaring - Prolonged Use

• If the ring has been left in place for up to 1 extra week:

– Remove, 1 week ring-free, insert new ring

• If the ring remains in place more than 4 weeks (>1 extra week):

– Remove, R/O pregnancy, restart with an additional contraceptive method until 7 days of continuous ring usage